In early 2007, Jeremy Sanders's group at the University of Cambridge reported the serendipitous discovery of a unique class of self-assembling, helical, organic nanotubes. Naphthalene diimide (NDI) derivatives, in which the aromatic core is flanked by two amino-acid residues, serve as the building blocks. Each turn of the helical nanotube consists of three NDI units oriented through hydrogen-bonding interactions. Although these NDI derivatives are readily synthesized, the nanotubes that form in solution are heterogeneous in length, dynamically disassembling and reforming. Thus, the first specific aim of the work proposed here is to exploit the synthetic simplicity and versatility of the Sanders system to prepare nanotubes of defined length. To achieve this goal, two complementary approaches will be pursued: One, the NDI monomers will be preorganized through the introduction of covalent tethers;and two, the ends of the nanotubes will be capped to prevent further association. In spring 2008, the Sanders group reported that in the presence of the buckminsterfullerene C70, their NDI derivatives assemble not into nanotubes but rather into discrete capsules containing six NDI subunits-that is, capsule formation is templated by C70. The second specific aim of this proposal is the generation of NDI capsules that form in the absence of template molecules. To achieve this goal, the NDI subunits will again be preorganized by the introduction of covalent tethers (in this case, capping is not also required since the untethered capsule itself is a discrete supramolecular complex). The tethering required to promote capsule formation is incompatible with nanotube formation, and thus the equilibrium for NDI subunit assembly should be shifted toward the formation of capsules. Finally, the third specific aim of this proposal is the synthesis of preorganized, tethered NDI constructs that form complexes with hydrophobic guests in aqueous solution-in water, hydrophobic guests should interact particularly favorably with the hydrophobic interior of the host NDI nanotubes and capsules. The discrete supramolecular complexes proposed here can be tailored for a variety of applications, and they may ultimately serve as delivery vehicles for drugs that otherwise exhibit poor pharmacokinetics. In addition, the preorganized assemblies may also serve as scaffolds for the creation of artificial enzymes. PUBLIC HEALTH RELEVANCE: Covalent tethering is proposed as a strategy to synthesize self-assembling molecular nanotubes and capsules of defined structure. These molecular assemblies may serve as delivery vehicles for drugs that otherwise exhibit poor pharmacokinetics. Ultimately, they may also serve as scaffolds for the creation of artificial enzymes.